Multifunctional gold clusterzymes with distinct glucose depletion and macrophage reprogramming capability towards regulating the regeneration cascade

Treating diabetic wounds remains a significant clinic challenge nowadays, where one of the major hurdles is hyperglycemia. Particularly, hyperglycemia sets off a cascade of changes in the wound microenvironment, which greatly impede the healing process, including an overproduction of glycation, excessive reactive oxygen species (ROS), increased vulnerability to infections, and persistent inflammation. To address these challenges, a novel type of multifunctional gold clusterzymes is designed, which display remarkable capabilities to deplete glucose, mitigate oxidative stress and attenuate inflammation. Gold nanoclusters co-engineered with lysozyme and curcumin (LC-AuNCs) exhibit exceptional glucose oxidase (GOx)-like activity and ROS-scavenging ability, which enable the efficient elimination of excess glucose without generating additional H₂O₂, thereby alleviating oxidative stress. Synergistic bactericidal effects of lysozyme and curcumin also endow LC-AuNCs with superior anti-infection activity. Notably, upon remodeling the wound microenvironment, LC-AuNCs could shift the macrophage toward M2 phenotype via MAPK/ERK/NF-κB and PI3K-AKT signaling pathways, as revealed by transcriptome sequencing analysis. Consequently, LC-AuNCs-incorporated hydrogels were fabricated, which could act as multifunctional dressings for regulating the regeneration cascade and promoting the healing of infected diabetic wound in vivo. Moreover, the inherent fluorescence property of LC-AuNCs enabled real-time monitoring of the healing process. The present study highlights the immense potential of engineered metal clusterzymes for biomedical applications, which also furnish an effective therapeutic strategy for glucose regulation and management of chronic wounds.